1. Field of the Invention
Provided herein are bone-derived extracellular matrix compositions, along with methods of making and using the compositions.
2. Description of Related Art
The extracellular matrix (ECM) of mammalian tissues can be isolated, decellularized and utilized as a biological scaffold. Biological scaffolds derived from tissues such as the small intestine, urinary bladder or dermis have been shown to facilitate functional restoration of different tissues, including heart and vascular structures, esophagus and musculo-skeletal tissues. The mechanisms by which constructive remodeling occur are well documented and include the recruitment of progenitor cells, promotion of cell migration and proliferation, regional angiogenesis and promotion of a favorable M2 macrophage phenotype at the interface of the host tissue and biological scaffold. Although these tissue-derived biological materials have been successfully used in non-homologous sites, recent studies have demonstrated “tissue specificity”, with the occurrence of additional functions and complex tissue formation when biological scaffolds were derived from site-specific homologous tissues.
Musculo-skeletal conditions are the most common cause of severe long-term pain and physical disability worldwide, with more than 3 million musculoskeletal procedures performed annually in the USA. Degenerative disease, severe infection, trauma and the excision of tumors can result in large non-healing defects in bone and other integrated tissues. Current treatment options for bone have limited effectiveness. Although autologous bone grafts are considered to be the gold standard with the best clinical outcome, significant limitations include restricted availability of donor tissue and morbidity at the harvest site. Shortcomings of allografts comprise issues of processing, sterilization, disease transmission and potential immunogenic response, with high rates of fractures and complications, attributed to their limited ability to revascularize and remodel.
Bone graft substitutes, such as demineralized bone matrix (DBM), have been developed to overcome the limitations of both autografts and allografts. Osteoconductive DBM is produced by the acid extraction of the mineral content from allogeneic bone and contains growth factors, non-collagenous proteins and type I collagen. While the osteoinductive effect of DBM has been well-documented in animal studies, albeit with variability (Peterson B, et al. Osteoinductivity of commercially available demineralized bone matrix preparations in a spine fusion model. J Bone Joint Surg 2004; 86:2243-50 and Wang J C, et al. A comparison of commercially available demineralized bone matrix for spinal fusion. Eur Spine J 2007; 16:1233-40), there is a paucity of similar information for human clinical studies (De Long W G, et al. Bone grafts and bone graft substitutes in orthopaedic trauma surgery: a critical analysis. J Bone Joint Surg 2007; 89:649-58), despite a robust clinical demand for DBM products. Differences in the preparation and processing methods and donor age all have an impact on DBM properties and clinical performance (Gruskin E, et al. Demineralized bone matrix in bone repair: history and use. Adv Drug Deliv Rev 2012; 64:1063-77). The end product of the demineralization process is a DBM powder.
To facilitate handling, formulation and reliable delivery clinically these particles are usually incorporated in a carrier. For example, the most common clinical form of DBM is a moldable putty, which involves formulation with a biocompatible viscous carrier that provides a stable suspension of DBM powder particles (Id.). The viscous carriers are generally either water-soluble polymers, such as sodium hyaluronate or carboxymethylcellulose, or anhydrous water-miscible solvents, such as glycerol. Studies designed to test the effectiveness of various carriers on DBM efficacy are limited. One study reported nephrotoxicity (Bostrom M P, et al. An unexpected outcome during testing of commercially available demineralized bone graft materials: how safe are the nonallograft components? Spine (Phila Pa. 1976) 2001; 26:1425-8) amidst speculation regarding glycerol as a carrier. Differences in osteogenic activity have also been observed (Peterson B, et al. J Bone Joint Surg 2004; 86:2243-50; Wang J C, et al. Eur Spine J 2007; 16:1233-40; and Acarturk T O, et al. Commercially available demineralized bone matrix compositions to regenerate calvarial critical-sized bone defects. Plast Reconstr Surg 2006; 118:862-73) which may be related to different carriers, the amount of DBM in the carrier and ability of the carrier to localize the DBM particulates to the bone defect site for a sufficient period of time to promote bone regeneration (Acarturk T O, et al. Plast Reconstr Surg 2006; 118:862-73). Additionally, a recent study characterized an inflammatory response to four commercial bone graft substitutes and found that the three DBM materials produced more inflammation than a synthetic hydroxyapatite compound. It was undetermined whether the DBM material or carrier provoked the inflammatory response (Markel D C, et al. Characterization of the inflammatory response to four commercial bone graft substitutes using a murine biocompatibility model. J Inflamm Res 2012; 5:13-8).